Submissions for variant NM_174936.4(PCSK9):c.1274A>G (p.Asn425Ser)

gnomAD frequency: 0.00485  dbSNP: rs28362261

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000297926	SCV000358248	likely benign	Hypobetalipoproteinemia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000417326	SCV000358249	likely benign	Hypercholesterolemia, autosomal dominant, 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417326	SCV000503511	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 / Software predictions: Benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454567	SCV000539996	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.7% (173/10272) African chromosomes
Invitae	RCV000417326	SCV000555875	benign	Hypercholesterolemia, autosomal dominant, 3	2024-02-01	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000336569	SCV000599431	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454567	SCV000699985	benign	not specified	2019-11-18	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1274A>G (p.Asn425Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 282818 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 171 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Additionally, association studies have shown that this variant is not associated with low or high cholesterol (Kotowski et al 2006). Co-occurrence with another pathogenic variant has been reported ((LDLR c.1257 C>G, Y419X) (Pisciotta_2006). In a functional study N425S was secreted normally, and had similar ability to reduce cell-surface LDLR as wild-type PCKSK9 (Fasano_2009). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (3x), likely benign (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001718599	SCV000730631	benign	not provided	2020-01-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20981092, 26332594, 26902539, 28965614, 16183066, 19081568)
Color Diagnostics, LLC DBA Color Health	RCV000776105	SCV000910948	benign	Familial hypercholesterolemia	2018-03-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000336569	SCV001135295	benign	Hypercholesterolemia, familial, 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374505	SCV002687501	benign	Cardiovascular phenotype	2018-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001718599	SCV004222363	benign	not provided	2020-01-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000417326	SCV004836720	benign	Hypercholesterolemia, autosomal dominant, 3	2024-02-05	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000776105	SCV005062049	benign	Familial hypercholesterolemia	2023-07-02	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000336569	SCV000606702	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research